Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by progressive cognitive deficiency or dysfunction and by early memory impairment of recent events. With the contemporary development of medical care and the increase in age of senile population, more economic and social costs are caused to be spent in the treatment or caring of patients with AD in the future. In the existing medical diagnostic techniques, neuropsychological assessment is frequently used for evaluation, including clinical measurements for evaluating the memory, lingual function, cognitive function, attention, and individual behaviors of AD patients. Such diagnostic methods lack the sensitivity and specificity for diseases, and are of limited significance for the treatment of patients, since the neuropathy in the brain is developed to a serious stage when the patients are detected to suffer from AD based on the assessment. Therefore, information about physiological functions may be provided by nuclear pharmaceutical agent in combination with positron emission tomography (PET) imaging, and the pathological status of the disease may be presented by nuclear imaging.
AD is characterized by progressive cognitive deficiency or dysfunction, and memory and executive dysfunction are accordingly the critical factors in early diagnosis in almost all the cases. However, the cerebral pathological changes originating from AD are present as early as ten to twenty years before the occurrence of cognitive decline or behavior change in the patients, and the pathological features are neurofibrillary tangles (NFTs) caused by seline plaques (SPs) of diffuse Aβ protein (β-amyloid), and hyperphosphorylated tau protein (Kung M P et al., 2004; Kulkarni P V et al, 2005). The tangles and plaques block the nerves from communication with each other and from signaling. The plaques are produced because the amyloid precursor protein (APP) cleavage enzyme cannot function properly, causing the β-cleavage enzyme and the γ-cleavage enzyme to alter the APP catabolic process, such that the beta amyloid is over produced (Routtenberg A et al, 1997). This type of protein is prone to aggregation, to form a precipitate, which may possibly lead to the beginning of neurodegeneration and decrease in secretion of neurotransmitter.
The formation of amyloid plaques is an early focus in development of AD, which occurs before cognitive impairment, memory difficulty, and symptoms as observed by FDG-positron emission tomography and MRI imaging, and earlier and more significant than the production of cerebrospinal fluid tau protein.
The most definitive diagnosis for AD is through Anatomy of the brain to observe pathological characteristics. Therefore, there is a need to determine whether the patients suffer from AD when alive by some molecular diagnostic techniques. In 2011, new diagnostic criteria and proposals are jointly published by National Institute on Aging (NIA) and Alzheimer's Association (AA), in which biomarkers are regarded as reference for inclusion in diagnostic criteria. The first class of diagnostic criteria include increased APβ protein deposition in the brain, decreased Aβ42 protein level in the cerebrospinal fluid, and positive reaction in the PET amyloid imaging. The second class of diagnostic criteria include persistently degenerated and injured nerve cells, including increased tau and phosphorylated tau (p-tau) protein level in the cerebrospinal fluid, weakened signal at the apical temporal lobe of the brain as shown by F-18 FDG-positron emission tomography, and particular atrophy at the temporal lobe and the inner apical lobe of the brain as shown by NMR imaging (see NTU Hospital Health Newsletter No. 73, December 2013). With the increasingly sophisticated nuclear imaging technology, if the early diagnosis of AD is available, treatment may be administered in the early stage of disease development, and the efficiency of the therapeutic agent in the clinical trial is increased. Also, the in-time diagnosis of the disease can allow their family members to have psychological preparation to give appropriate care, and reduce the discomfort of patients to improve the quality of life. Therefore, development of new drugs for AD is still a topic to which unremitting efforts are made by the scientists.
Abnormal accumulation of β-amyloid in the brain is believed to be the main cause of loss of memory in the patients. As such, some therapeutic agents under development target at this protein, and are expected to inhibit the undesirable production or reduce the undesirable accumulation of the protein. However, a bottleneck is encountered in the development of drugs for AD. That is, the patients with AD are diagnosed only after the clinical symptoms are displayed, and at this time, too much non recoverable damage is accumulated in the brain of the patients. Accordingly, it is necessary and urgent to develop an early diagnostic tool both in the study of the role of β-amyloid in AD and in the detection of the progression of AD.
In the past, in-vivo non-invasive study of glucose metabolism in the brain by using PET with F-18 FDG (2-deoxy-2-[F-18]fluoro-D-glucose) has a history of over 25 years (Nakamura S et al., 2001). It is found in the study using PET/F-18 FDG that in the AD patients, a clinical symptom of considerably reduced metabolism of F-18 FDG at the position of the focus is shown. The reduced absorption of F-18 FDG occurs even ahead of the cognitive dysfunction, and is positively correlated with the severity of dementia. Although F-18 FDG provides some interpretations with respect to metabolism, these interpretations cannot indicate the specific position of the lesion in the brain (Lee C W et al., 2003) or are not specific function tests for AD patients (Ye L et al., 2006).
In recent years, the nuclear pharmaceuticals and positron emission tomography (PET) imaging are developed remarkably. The contrast agent C-11 PiB (Pittsburgh Compound B) having a high affinity to β-amyloid is specifically used in the detection of β-amyloid, or the deposition of β-amyloid may be quantified by imaging. However, the half-life of C-11 is only 20 min, and the produced agent cannot be shipped to other hospitals for use, is limited to entities having cyclotron, and cannot be commercialized. Therefore, to seek a more stable and specific contrast agent, F-18 tagged PiB (Flutemetamol, GE Healthcare), F-18-AV-45 (Florbetapir, AVID-RP/Lilly) and F-18-AV-1 (Florbetaben, Piramal) enter clinical trial in succession. The F-18 has a half-lie of up to 110 min, a high energy, and a good sensitivity, and can be shipped. In addition, the contrast agent for dementia under development at present further includes Azd4694 (Navidea). These contrast agents all suffer from some drawbacks, for example, some sub-regions cannot be detected, the specificity remains to be tested and there is no consistent determination standards for clinical diagnosis. Moreover, considering the patent right, the clinical trial can be conducted at home only at the allowance of the above enterprises and by purchase from the manufacturer. The royalty payment is enormous over a long period of time, resulting in a high imaging cost, and the imaging cannot be a routine test. Domestic research and development of the contrast agent is more cost-effective and conducive to the improvement of the caring quality of the patients.
In view of the foregoing, by screening by computer simulation and validating the ability of compounds to bind to amyloid through in-vitro binding ability assay, the N-(4-isopropylphenyl)-5-amino-isoindoline is screened out, which can be used for detection of AD in-vivo. In this way, the present invention is accomplished.